An overview of QT interval assessment in safety pharmacology.
Authors: Guillaume P, Goineau S, Froget G
Abstract
Medicinal products that prolong cardiac repolarization, as assessed in terms of prolongation of the QT interval of the electrocardiogram, may trigger torsade de pointe, a potentially fatal arrhythmia. The lethality of this risk necessitates a detailed preclinical evaluation before initiating clinical trials. The strategy for assessing the potential of new chemical entities to cause QT interval prolongation involves two complementary approaches. An in vivo test provides information on the potential of the agent to prolong the QT interval under near-physiolo...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Overview of cancer stem cells (CSCs) and mechanisms of their regulation: implications for cancer therapy.
Authors: Bao B, Ahmad A, Azmi AS, Ali S, Sarkar FH
Abstract
The identification of small subpopulations of cancer stem cells (CSCs) from blood mononuclear cells in human acute myeloid leukemia (AML) in 1997 was a landmark observation that recognized the potential role of CSCs in tumor aggressiveness. Two critical properties contribute to the functional role of CSCs in the establishment and recurrence of cancerous tumors: their capacity for self-renewal and their potential to differentiate into unlimited heterogeneous populations of cancer cells. These findings suggest that CSCs may represent novel therapeut...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Primary human non-small cell lung and pancreatic tumorgraft models--utility and applications in drug discovery and tumor biology.
Authors: Calles A, Rubio-Viqueira B, Hidalgo M
Abstract
The number of therapeutic options for lung and pancreatic cancer is increasing because of the identification of new druggable molecular targets and development of new drug combinations. Reproducible, biologically relevant in vivo pre-clinical models are critical for this effort. The generation of patient-derived tumor xenografts has proven useful for integrating drug screening with biomarker discovery, discovering fundamental information in tumor biology, prioritizing drugs for clinical investigation, and personalizing treatments for these tumors. The...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Models of depression: unpredictable chronic mild stress in mice.
Authors: Nollet M, Le Guisquet AM, Belzung C
Abstract
Major depression is a complex psychiatric disorder characterized by affective, cognitive, and physiological impairments that lead to maladaptive behavior. The high lifetime prevalence of this disabling condition, coupled with limitations in existing medications, make necessary the development of improved therapeutics. This requires animal models that allow investigation of key biological correlates of the disorder. Described in this unit is the unpredictable chronic mild stress mouse model that is used to screen for antidepressant drug candidates. Origi...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Overview of Electrophysiological Techniques.
Authors: Wickenden AD
Abstract
This unit provides an overview of the principal electrophysiological techniques commonly used for the study of ionic currents and the ion channels that mediate them. These techniques include electroencephalograms (EEGs), electrocardiograms (ECGs), single- and multiunit extracellular recording, multielectrode arrays, transepithelial recording, impedance measurements, and current-clamp, voltage-clamp, patch-clamp, and lipid bilayer recording. The unit also discusses recent advances in high-throughput, automated electrophysiological techniques for drug discovery and the use of s...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Electrophysiological Techniques for Studying Synaptic Activity In Vivo.
Authors: Jeggo R, Zhao FY, Spanswick D
Abstract
Understanding the physiology, pharmacology, and plasticity associated with synaptic function is a key goal of neuroscience research and is fundamental to identifying the processes involved in the development and manifestation of neurological disease. A diverse range of electrophysiological methodologies are used to study synaptic function. Described in this unit is a technique for recording electrical activity from a single component of the central nervous system that is used to investigate pre- and post-synaptic elements of synaptic function. A strength of t...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
A High-Throughput (HTS) Assay for Enzyme Reaction Phenotyping in Human Recombinant P450 Enzymes Using LC-MS/MS.
Authors: Li X, Suhar T, Glass L, Rajaraman G
Abstract
Enzyme reaction phenotyping is employed extensively during the early stages of drug discovery to identify the enzymes responsible for the metabolism of new chemical entities (NCEs). Early identification of metabolic pathways facilitates prediction of potential drug-drug interactions associated with enzyme polymorphism, induction, or inhibition, and aids in the design of clinical trials. Incubation of NCEs with human recombinant enzymes is a popular method for such work because of the specificity, simplicity, and high-throughput nature of this approach f...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Characterization of P1 (adenosine) purinoceptors.
Authors: Jarvis MF
Abstract
The purine nucleoside adenosine (ADO) is an important modulator of cellular function in mammalian tissues, modulating cellular function and neuronal excitability via interactions with different cell surface receptor subtypes that are heterogeneously distributed in both the mammalian CNS and peripheral tissues. Four ADO receptor subtypes have been cloned and characterized. Described in this unit are three radioligand binding assays for pharmacological characterization of the high-affinity ADO receptor subtypes A1, A2A, and A3 receptors. Pharmacological characterization of the low...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Harvesting, isolation, and functional assessment of primary vagal ganglia cells.
Authors: Dubuis E, Grace M, Wortley MA, Birrell MA, Belvisi MG
Abstract
Airway sensory nerves play an important defensive role in the lungs, being central in mediating protective responses like cough and bronchoconstriction. In some cases, these responses become excessive, hypersensitive, and deleterious. Understanding the normal function of airway nerves and phenotype changes associated with disease will help in developing new therapeutics for treating chronic obstructive pulmonary disease and chronic cough. Guinea pigs, and to a lesser extent ferrets, are commonly employed for studying the cough reflex b...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Utility and applications of orthotopic models of human non-small cell lung cancer (NSCLC) for the evaluation of novel and emerging cancer therapeutics.
Authors: Justilien V, Fields AP
Abstract
Lung cancer is a leading cause of cancer deaths worldwide. Despite advances in chemotherapy, radiation therapy, and surgery, lung cancer continues to have a low 5-year survival rate, highlighting a dire need for more effective means of prevention, diagnosis, prognosis, and treatment. Mouse models that recapitulate the clinical features of advanced human lung cancer are critical for testing novel therapeutic approaches. This unit describes a highly reproducible, easy-to-establish orthotopic murine model of lung cancer, provides methods for in vivo imaging and monitor...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Overview of experimental models of the blood-brain barrier in CNS drug discovery.
Authors: Palmer AM, Alavijeh MS
Abstract
The blood-brain barrier (BBB) is a physical and metabolic entity that isolates the brain from the systemic circulation. The barrier consists of tight junctions between endothelial cells that contain egress transporters and catabolic enzymes. To cross the BBB, a drug must possess the appropriate physicochemical properties to achieve a sufficient time-concentration profile in brain interstitial fluid (ISF). In this overview, we review techniques to measure BBB permeation, which is evidenced by the free concentration of compound in brain ISF over time. We consider a nu...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Characterization of the picrotoxin site of GABAA receptors.
Authors: Mehta AK, Ticku MK
Abstract
This unit describes an in vitro assay for characterization of the picrotoxin site of GABAA receptors in rat brain membranes using various radioligands. Methods and representative data for Scatchard analysis (Kd, Bmax determination), association kinetics, dissociation kinetics, and competition assays (IC50, Ki determination) are included.
PMID: 24510752 [PubMed - indexed for MEDLINE] (Source: Current Protocols in Pharmacology)
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Characterization of cannabinoid receptors.
Authors: Cox RF, Rash V
Abstract
This unit describes the use of cannabinoid radioligands in competitive binding assays for determining affinity parameters (IC50, Ki ) of unlabeled compounds at transfected CB1 and CB2 receptors expressed in cell lines.
PMID: 24510753 [PubMed - indexed for MEDLINE] (Source: Current Protocols in Pharmacology)
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Characterization of GABA receptors.
Authors: Enna SJ, McCarson KE
Abstract
Described in this unit are ligand-binding assays for GABAA , GABAB , and the homomeric ρ GABAA (formerly GABAC ) receptor recognition sites in brain tissue. Although GABA binding sites are present in peripheral organs, most research is directed toward examining these receptors in the CNS. These assays may also be used to determine the affinity of an unlabeled compound for the GABA binding sites. Excluded from the unit are ligand-binding assays for other components of the GABAA receptor complex, such as the benzodiazepine or ion-channel binding sites.
PMID: 24...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
Overview of safety pharmacology.
Authors: Goineau S, Lemaire M, Froget G
Abstract
Safety pharmacology entails the assessment of the potential risks of novel pharmaceuticals for human use. As detailed in the ICH S7A guidelines, safety pharmacology for drug discovery involves a core battery of studies on three vital systems: central nervous (CNS), cardiovascular (CV), and respiratory. Primary CNS studies are aimed at defining compound effects on general behavior, locomotion, neuromuscular coordination, seizure threshold, and vigilance. The primary CV test battery includes an evaluation of proarrhythmic risk using in vitro tests (hERG channe...
Source: Current Protocols in Pharmacology - November 18, 2015 Category: Drugs & Pharmacology Tags: Curr Protoc Pharmacol Source Type: research
